Pompe disease is an example of a lysosomal storage disorder. Pompe disease is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). GAA metabolizes glycogen, a storage form of sugar used for energy, into glucose. The accumulation of glycogen is thought to lead to progressive muscle myopathy throughout the body which affects various body tissues, particularly the heart, skeletal muscles, liver, and nervous system. According to the National Institute of Neurological Disorders and Stroke, Pompe disease is estimated to occur in about 1 in 40,000 births.
There are three recognized types of Pompe disease—infantile, juvenile, and adult onset. Infantile is the most severe, and presents with symptoms that include severe lack of muscle tone, weakness, enlarged liver and heart, and cardiomyopathy. Swallowing may become difficult and the tongue may protrude and become enlarged. Most children die from respiratory or cardiac complications before the age of two. Juvenile onset Pompe disease first presents in early to late childhood and includes progressive weakness of the respiratory muscles in the trunk, diaphragm, and lower limbs, as well as exercise intolerance. Most juvenile onset Pompe patients do not live beyond the second or third decade of life. Adult onset symptoms involve generalized muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm. Some adult patients are devoid of major symptoms or motor limitations.
Enzyme replacement therapy (ERT) is one approach to treating Pompe Disease. One of the main complications with ERT is the attainment and maintenance of therapeutically effective amounts of enzyme due to rapid degradation of the infused enzyme. As a result, ERT requires numerous, high-dose infusions and is costly and time consuming
A newer approach to treating Pompe Disease, a specific chaperone strategy, rescues mutated proteins from degradation presumably in the endoplasmic reticulum (ER) or in other cellular protein degradation/disposal systems. This strategy employs small molecule reversible inhibitors which specifically bind to a defective lysosomal enzyme associated with a particular lysosomal disorder. The chaperone strategy involves the use of a small molecule that facilitates the correct folding of a mutated protein, to prevent undue or abnormal degradation from the ER quality control system. These specific chaperones are designated as active site-specific chaperones. See, e.g., U.S. Pat. Nos. 6,274,597, 6,583,158, 6,589,964, and 6,599,919, each of which incorporated by reference herein. U.S. Pat. No. 6,583,158 discloses 1-deoxynojirimycin (DNJ) and other active site-specific chaperones for treating Pompe Disease.
1-DNJ can be provided in a solid form for oral administration. However, if DNJ is to be administered as part of a combination therapy along with ERT, there is a desire for parenterally administered DNJ, as a parenteral formulation allows for greater dosage control and administration access. Also, patients, expecially infants, may have difficulty swallowing oral dosage forms, regardless of whether monotherapy or combination therapy is elected as a form of treatment. Although 1-DNJ is soluble and generally stable in aqueous formulations, such formulations are not suited for parenteral administration because of the need for pH control over a practical shelf-life of the formulation and to provide a suitable osmolality for parenteral administration such that the formulation does not cause deleterious health effects.